The overall goal of this project is to develop biomarkers for Parkinson's Disease (PD) using metabolomic profiling. PD is the second most common neurodegenerative disease affecting about 1 million individuals in the United States. The development of biomarkers for PD would have tremendous utility to identify individuals at risk at the pre-clinical stage of disease, provide diagnostic and surrogate markers of disease and its progression. Metabolomics is the comprehensive measurement of the small signaling and process control molecules in the body that reflect at any given time the interaction of genetic and environmental factors. In preliminary studies we analyzed metabolomic profiles from plasma of control subjects (n=50), subjects with PD (n=120), Amyotrophic Lateral Sclerosis (ALS) (n=30) and Huntington's disease (HD) (n=35). We created a database from the ca. 2000 compounds measured with the Liquid Chromatography Electrochemical Array platform (LCECA). We analyzed this data and found a set of markers that distinguish unmedicated PD subjects from controls. We used the markers to show a shift in metabolomic profiles of PD subjects on different medications which indicated the possibility of metabolomic subgroups in PD. Similarly, using metabolomic profiles, we showed complete metabolomic categorical separation of subjects with PD, HD and ALS. In this work we propose to apply metabolomics approach to develop biomarkers for PD that will allow diagnosis, monitoring of progression and evaluation/selection of therapy. We will use our analytical platforms to analyze samples from control subjects and from idiopathic PD patients, as well as from PD patients with LRRK2 mutations and appropriate controls. We will examine metabolomic profiles of PD patients in relation to control subjects in relationship to diagnostic and clinical data in order to establish metabolomic profiles and specific biomarkers characteristic for PD. Using LC Mass Spectrometry (LCMS) and integrated LCECA/LCMS approaches we will obtain structural information for PD biomarkers. This project will apply metabolomics approach to develop biomarkers for Parkinson's Disease. [unreadable] [unreadable] [unreadable]